Multiple sclerosis (MS) is a complex and heterogeneous inflammatory disorder of the central nervous system (CNS) characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. MS is the most common cause of acquired neurological disability in the U.S. and European countries arising during early and mid-adulthood, and it affects more than one million people worldwide. The goal of this proposal is to identify genetic factors and complex interactions between genetic and non- genetic risk factors that predispose to MS and related phenotypes. We describe for the very first time in MS, a powerful and novel approach to pursue well-defined hypotheses based on strong preliminary data that are critical to furthering our understanding of disease pathogenesis. A major focus of this proposal will be the identification of complex risk factors that (a) predispose to the autoimmune prone MS phenotype, and (2) distinguish between MS subgroups defined by the presence or absence of the well-established disease associated HLA-DRB1*15 genotype and other environmental exposures, and (c) the application of novel and powerful analytical tools to identify complex relationships, including interactions, between large numbers of potential risk factors that can predict disease status or related phenotypes. We will study a large, well characterized population-based MS case- control data set comprised of 2,400 individuals. We will use well-established strict ascertainment criteria for MS cases and a suite of sophisticated tools including electronic database surveying, direct physician contact, chart review and comprehensive interviews to determine definite MS diagnoses and important phenotypic designations for this study. State of the art high-throughput genotyping of more than 550,000 informative single nucleotide polymorphisms will be performed. The complete elucidation of genetic and non- genetic influences underlying disease risk and heterogeneous MS phenotypes would clearly play a major role in understanding disease biology and would contribute significantly to disease prevention and the development of targeted and more effective therapeutics. PROJECT NARRATIVE Multiple sclerosis (MS) represents a physical, emotional, social and fiscal burden to the health care system and like other autoimmune disorders is a significant public health concern resulting in lost productivity and decreased quality of life. Fifteen years after diagnosis, less than 20% of patients have no functional limitations; 50-60% require ambulating assistance, at least 70% are unable to perform normal daily activities, and 75% are unemployed. The complete elucidation of genetic and non-genetic influences underlying MS would clearly play a major role in understanding disease biology and would contribute significantly to disease prevention and the development of targeted and more effective therapeutics.